LB0004 Paediatric Systemic Lupus Erythematosus (pSLE) patient stratification and high-performance serum biomarkers identified responders to statin and patients with high cardiovascular risk in the APPLE trial (Atorvastatin for Atherosclerosis Progression in Paediatric Systemic Lupus Erythematosus)
Authors: C. Ciurtin, J. Peng, P. Donnes, L. Lewandowski, S. Ardoin, L. Schanberg, G. Robinson, E. Jury
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Paediatric Systemic Lupus Erythematosus (pSLE) is associated with increased risk of atherosclerosis compared to adult-onset SLE. The APPLE trial is the largest investigator-led randomised control trial in pSLE, which tested the effect of atorvastatin vs. placebo for prevention of atherosclerosis progression over 36 months, using carotid intima-media thickness (CIMT) as primary outcome. <h3>Objectives</h3> We aimed to investigate: 1. patient stratification strategies to identify responders to statin in a trial which did not meet the primary outcome as well as. 2. novel high-performance biomarkers of atherosclerosis progression in the APPLE trial to establish which pSLE patients were at risk for atherosclerosis progression even if they did not respond to statin. <h3>Methods</h3> Unsupervised clustering analysis was used to stratify pSLE patients by their baseline CIMT and identify patterns of CIMT progression over 36 months. In-depth metabolomic analysis was performed to identify lipidomic signatures predictive of CIMT progression in both placebo and statin arm. Correlation and univariate regression analyses explored associations between patient, disease characteristics and serum biomarkers (Nightingale platform). Machine learning techniques and ROC analyses were used to identify and validate a serum metabolomic signature of high CIMT progression. <h3>Results</h3> Baseline CIMT stratified pSLE patients (N=151) into three groups with distinct CIMT progression trajectories irrespective of the treatment allocation. Two distinct CIMT progression rates (high vs. low), over 36 months were identified in the placebo group (N=60), while patients treated with atorvastatin (N=61) had three distinct CIMT trajectories (high, intermediate and low progression), not predicted by any of the numerous patient and disease determinants, including serum biomarkers, lipid profile and homocysteine levels, collected as part of the APPLE trial protocol. A robust and novel metabolomic signature predictive of high CIMT progression was identified (AUC = 80.7%) in the placebo arm, which could be used to identify patients at risk of atherosclerosis progression in pSLE. pSLE patients with low rate CIMT progression identified by the CIMT stratification benefitted from treatment with atorvastatin (P= 0.035), providing evidence that the lack of patient stratification led to the negative results of the APPLE trial. <h3>Conclusion</h3> This analysis of the APPLE trial provides novel evidence for the significant heterogeneity of subclinical atherosclerosis in pSLE and its distinct progression trajectories irrespective of treatment allocation, and identified pSLE patients who responded to statin, with implications for future patient stratification for clinical trials. We also showed that in- depth metabolomic signature can identify with better performance that any other biomarkers available, patients at risk for atherosclerosis progression with potential role for long-term cardiovascular risk management in pSLE. <h3>REFERENCES</h3> <b>NIL</b>. <h3>Acknowledgments</h3> Childhood Arthritis and Rheumatology Research Alliance. <h3>Disclosure of Interests</h3> None Declared.